Dementia has been widely recognized as a very serious health problem. Alzheimer's disease, which has been identified by the National Institutes of Aging as accounting for more than 50% of dementia in the elderly, is also the fourth or fifth leading cause of death in Americans over 65 years of age. Four million Americans, 40% of Americans over age 85 (the fastest growing segment of the U.S. population), have Alzheimer's disease. Twenty-five percent of all patients with Parkinson's disease also suffer from Alzheimer's disease-like dementia. And in about 15% of patients with dementia, Alzheimer's disease and multi-infarct dementia coexist. The third most common cause of dementia, after Alzheimer's disease and vascular dementia, is cognitive impairment due to organic brain disease related directly to alcoholism, which occurs in about 10% of alcoholics.
The precise molecular lesion(s) that contribute to the morphological and functional deficits associated with dementia is unclear despite intensive research efforts over the last decade. However, the most consistent abnormality for Alzheimer's disease, as well as for vascular dementia and cognitive impairment due to organic brain disease related to alcoholism, is the degeneration of the cholinergic system arising from the basal forebrain (BF) to both the codex and hippocampus (Bigl et al., in Brain Cholinergic Systems, M. Steriade and D. Biesold, eds., Oxford University Press, Oxford, 1990, pp. 364-386). In particular, neurochemical evidence from the brains of patients afflicted with Alzheimer's disease has revealed reliable decreases in markers of cholinergic neuronal function (Perry et al., Br. Med. J. 1978, 2:1457; Reisine et al., Brain Res. 1978, 159:477; Coyle et al., Science 1983, 219.1184; and McGeer et al., Neurology 1984, 34:741). While there are a number of other neurotransmitter systems affected by Alzheimer's disease (Davies, Med. Res. Rev. 1983, 3.221), the relative occurrence of such abnormalities is less consistent or the effect is less profound than the decreases in these cholinergic neuronal function markers. More specifically, substantial reductions (30-50%) in nicotinic cholinergic receptors have been consistently reported in the brains of patients with Alzheimer's disease or Parkinson's disease (Kellar et al., Brain Res., 1987, 436:.62; and Whitehouse et al., Neurol 1988, 38:720), whereas changes in muscarinic cholinergic receptors are less remarkable and more dependent on receptor subtype.
However, degeneration of the cholinergic neurotransmitter system is not limited to individuals suffering from dementia. It has also been seen in otherwise healthy aged adults and rats. Decreases in cholinergic markers in the basal forebrain, decreases in cortical activities of the biosynthetic and degradative enzymes for acetylcholine, decreases in the ability to release acetylcholine from tissue slices, and decreases in numbers of cortical nicotinic receptors have all been reported in such otherwise healthy aged individuals (for a review, see Giacobini, J. Neurosci. Res. 1990, 27:548). Moreover, for those cholinergic neurons that remain, aging may cause a decrease in the temporal fidelity of existing impulse flow from the basal forebrain to the cortex (Aston-Jones et al., Brain Res. 1985, 325:271). Consistent with these findings are pharmacological studies suggesting that cholinergic mechanisms are, at least in part, responsible for the memory disturbances in aged animals and humans not suffering from Alzheimer's disease (Drachman and Leavitt, Arch. Neurol. 1974, 30:113; Bartus et al., Science 1982, 217:408).
Other clinical correlates associated with the neurodegenerative process of Alzheimer's disease include decreases in regional cerebral blood flow and cerebral glucose utilization, in regions which largely parallel the areas where cholinergic deficits occur (Ingvar and Risberg, Exp. Brain Res., 1962, 3:195; Ingvar et al., Aging: Alzheimer's Disease, Senile Dementia and Related Disorders, Vol. 7, R. Katzman, R. D. Terry, and K. L. Bick, eds., Raven Press, 1978, p. 203; and Dastur, J. Cerebral Blood Flow & Metabol., 1985, 5:1). In fact, it has been suggested that routine measurement of cerebral blood flow may be a useful procedure in evaluating patients suspected of having dementia, and of having Alzheimer's disease in particular.
Conflicting reports exist regarding the effect of aging on resting cerebral blood flow and cerebral glucose utilization in "normal, healthy" aged humans (Dastur, J. Cerebral Blood Flow & Metabol. 1985, 5:1, ) and rats (Smith et al.,Brain , 1980, 103:351; and Buchweitz-Milton and Weiss, Neurobiol. Aging, 1987, 8:55). Although decreases in cerebral blood flow and cerebral glucose utilization are generally reported in aged populations, it has been suggested that these decreases are secondary to other ongoing cerebral dysfunctions. Nonetheless, deficiencies in metabolic and cerebrovascular responses to pharmacologic and physiologic perturbation are consistently reported. Of particular interest is the recent finding in rats that increases in cerebral blood flow elicited by electrical stimulation of the basal forebrain shows age-related impairments (Linville and Arneric, Soc. Neurosci. Abstract, 1989, 15:17.5). Indeed, studies that compare the degree of learning impairment with the degree of reduced cortical cerebral blood flow in aged rats show a good correlation (Berman et al., Neurobiol. Aging, 1988, 9:691).
Recent clinical evidence suggests that the characteristic perfusion abnormality observed in Alzheimer's disease patients reflects regional nicotinic cholinergic deficits (Prohovnik, Neurobiol. Aging, 1990, 11:262). In particular, mecamylamine, a centrally-acting nicotinic receptor antagonist, reduces resting cortical perfusion in the parietotemporal cortex of humans, the area of the cortex most consistently found to be impaired in functional brain imaging of Alzheimer's disease patients. In agreement with this finding, regulation of cerebral blood flow in the frontoparietal cortex, governed by the basal forebrain, is also dependent upon nicotinic mechanisms in the rat (Arneric, J. Cerebral Blood Flow & Metabol., 1989, 9 (Suppl. 1): S502).
Chronic alcoholism, more particularly, the resultant organic brain disease, like Alzheimer's disease and normal aging, is also characterized by diffuse reductions in cortical cerebral blood flow in those brain regions where cholinergic neurons arise (basal forebrain) and to which they project (cerebral cortex) (Lofti & Meyer, Cerebrovasc. and Brain Metab. Rev, 1989, 1:2). Moreover, of all the neurotransmitter systems studied, the neurotoxic effects of alcohol on the cholinergic system are thought to be the most important.
Intuitively, regardless of specific etiologic process, therapies directed towards enhancing cognitive processing would be contingent upon maintaining a well-regulated balance between adequate cerebral blood flow, cerebral glucose utilization and cholinergic neurotransmission arising from the basal forebrain.
Pilot clinical studies suggest that nicotine may be useful for the acute treatment of deficits in attention and information processing associated with Alzheimer's disease (Sahakian et al., Brit. J. Psych., 1989, 154:797; Newhouse et al., Psychopharmacol., 1988, 95:171). It has been shown that both acutely and chronically-administered nicotine enhances cognitive function in rats (Levin et al., Behav. Neural Biol., 1990, 53.269), an effect that is also observed in aged animals (Cregan et al., Soc. Neurosci. Abstract, 1989, 15: 2952). Anecdotal evidence suggests a negative correlation between smoking by an individual and the likelihood of the individual acquiring Alzheimer's disease. These findings are supported by additional animal studies demonstrating a neuroregenerative/neuroprotective action of chronically-administered nicotine on both neuronal and vascular functions following hemitransection or MPTP-induced destruction of the nigro-striatal dopamine system (Janson et al., Prog. Brain Res., 1989, 79:257; and Owman et al., Prog. Brain Res., 1989, 79:267). Interestingly, in contrast to the classical down-regulation of receptors typically seen with receptor agonists, chronic nicotine administration up-regulates (50-100%) the number of receptors without affecting affinity (Benwell et al.,J. Neurochem., 1988, 50:1243). This effect occurs both in humans and in smaller animals such as rats (Lapchack et al., J. Neurochem., 1989, 52. 483 ).
Existing cholinergic agonists, however, are therapeutically sub-optimal. This is due to unfavorable pharmacokinetics (e.g., with arecoline and nicotine), poor potency and lack of selectivity (e.g., with RS-86), poor CNS penetration (e.g., with carbachol) or poor oral bioavailability (e.g., with nicotine). RS-86, for example, has similar affinity for cholinergic receptors located in the heart and in cortical tissues and is a full agonist at cardiac receptors, whereas it is only a partial agonist at cortical receptors (S. B. Freedman, British Journal of Pharmacology, 1986, 87: 29P). In addition, known agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor and peripheral side effects, including miosis, lacrimation, defecation and tachycardia (Benowitz et al., in: Nicotine Psychopharmacology, S. Wonnacott, M. A. H. Russell, & I. P. Stolerman, eds., Oxford University Press, Oxford, 1990, pp. 112-157; and M. Davidson, et al., in Current Research in Alzheimer Therapy, E. Giacobini and R. Becker, ed.; Taylor & Francis: New York, 1988; pp 333-336).
In addition to treating decline in cognitive ability by improving cholinergic function and cerebral blood flow, it is also desirable to symptomatically treat the other mental disorders accompanying the earlier stages of Alzheimer's disease. Anxiolytics have been used to treat the severe agitation that most Alzheimer's patients experience with the initial loss of memory (INPHARMA, March 16, 1991, pg 20). In fact, the use of anxiolytics has become an important aspect of treatment strategies for Alzheimer's disease (Schmidt et al., Drug Dev. Res., 1988, 14:251). Nicotine is known to have anxiolytic properties (Pomerleau et al., Addictive Behaviors, 1984, 9:265) and, therefore, nicotine or selective nicotine agonists may be useful in the treatment of the anxiety associated with dementias, such as Alzheimer's disease.
The neurotoxic effect of alcohol on the cholinergic system, discussed above, suggests that neuronal nicotinic receptor ligands, such as the novel compounds of the present invention, may therefore also be useful in the treatment of individuals suffering from acute alcohol intoxication, one of the most critical of medical emergencies. Without an effective treatment, an individual suffering from this condition may go into a coma or die, and unfortunately, few drug treatments for this condition are available to the emergency room physician.
Several drugs, such as amphetamine, picrotoxin, niketamide and caffeine, have been used in the past in order to treat acute alcohol intoxication (Lister & Nutt, Trends in Neuroscience, 10: 223, 1987). These treatments have met with little success due to the narrow therapeutic window of these agents. RO 15-451 3, a benzodiazepine receptor inverse agonist, has been reported to selectively antagonize the effects of ethanol in rats (Suzdak et al., Science, 234: 1243-1247, 1986), but the development of this compound for human use was discontinued because of its proconvulsant activity (Lister & Nutt, Trends in Neuroscience, 10: 223, 1987).
Recently, (-)-nicotine administered directly into the brains of rats was shown to significantly attenuate the motor incoordination due to the effects of ethanol administered intraperitoneally (Dar et al., Brain Res. Bull., 32:23-28, 1993). However, direct injection into the human brain is not a clinically-acceptable route of administration for routine use in a hospital or emergency room, and it is unclear whether these beneficial properties can be obtained using a more direct, more routine and clinically-acceptable route of systemic administration, such as intraperitoneal, intramuscular, intravenous, topical or oral delivery of the drug. The present application demonstrates that the novel neuronal nicotinic receptor ligands disclosed herein are effective in reducing ethanol narcosis when administered systemically (intraperitoneal delivery), whereas (-)-nicotine is not.
Other situations where beneficial therapeutic outcome may be achieved or improved through administration of nicotine or a nicotine agonist, because of the anxiolytic properties of these agents, include attentional deficit disorder, petit mal absence epilepsy and drug withdrawal.
Attention-deficit disorder (ADD), with or without hyperactivity, is a behavioral disorder characterized by distractibility and impulsiveness. Children with this disorder are handicapped by their inability to concentrate and control their impulsivity, especially in settings requiring sustained attention, for example, in school. While a cure for this disorder has not been found, stimulants, such as pemoline, have been used successfully in management of the behavioral manifestations of ADD. Nicotine, because of its ability to improve concentration and task performance (F. T. Etscorn, U.S. Pat. No. 4,597,961, issued Jul. 1, 1986; and D. M. Warburton and K. Wesnes in Smoking Behavior, R. E. Thornton, ed., Churchill-Livingston, Edinburgh, 1978, pp. 19-43) is also potentially useful in treating ADD.
Another situation where beneficial therapeutic outcome may be achieved or improved through administration of a neuronal nicotinic receptor ligand, because of the ability of these agents to control or prevent spike wave discharges associated with petit mal absence and impairments of mental function, include petit mal absence epilepsy.
Petit mal absence is a form of epilepsy characterized by lapses of consciousness that result in impairments of mental function. The five-second-to-two-minute attacks are accompanied by a blank facial stare with little or no apparent muscle activity, in sharp contrast to the massive tonic-clonic spasms of the entire body typical of grand mal epilepsy. Electroencephalographic (EEG) records of both grand mal and petit mal absence epilepsy patients are complex, but one diagnostic feature of the latter is a three-Hertz spike wave discharge not seen in grand mal. Petit mal absence epilepsy first appears in children four years of age or slightly older, but generally declines as the child goes through adolescence. The lapse of attention associated with petit mal absence can, however, be a significant problem in school age children. In a few cases, petit mal absence develops into primary generalized epilepsy during adulthood (Niedermeyer, in E. Niedermeyer and F. Lopes da Silva, eds., Electroencephalography, Basic Principles, Clinical Application and Related Fields, 1987, pp. 405-510). Currently-prescribed agents which attenuate spike wave discharges, such as benzodiazepines, unfortunately also produce undesirable side effects such as sedation and/or memory loss.
Tobacco use, especially cigarette smoking, has long been recognized as a major factor leading to disease and death. Approximately 4,000 by-products of combustion, many of which are known carcinogens, have been found in cigarette smoke. Of the three most-studied constituents of cigarette smoke, two, tars and carbon monoxide, have been found to cause or exacerbate numerous life-threatening disorders. Tars are most often implicated in the induction of lung, larynx, oral cavity, esophageal and other cancers, and are also thought to be responsible for respiratory diseases, including pulmonary emphysema, chronic bronchitis and smokers respiratory syndrome. Carbon monoxide, on the other hand, combines with hemoglobin in the blood thereby decreasing the ability of the blood to carry oxygen, and it has also been implicated as a causative agent in the development of coronary artery disease and arteriosclerosis. The third highly-studied, and the most pharmacologically-active substance, in tobacco products is nicotine, which is the reinforcing agent responsible for maintaining tobacco dependency and therefore exposing smokers to other threats of tobacco use (J. H. Jaffe in Nicotine Pharmacology: Molecular, Cellular and Behavioral Aspects, S. Wonnacott, M. A. H. Russell and I. P. Stolerman, eds., Oxford Science Publications, Oxford, 1990, pp. 1-37).
The nicotine withdrawal syndrome associated with smoking cessation is characterized by craving for nicotine, irritability, frustration or anger, anxiety, difficulty concentrating, restlessness, decreased heart rate and increased appetite and weight gain. Nicotine has, not surprisingly, been found to ease the withdrawal experienced by those attempting to break tobacco dependencies. As early as 1942, Johnston reported (L. Johnston, Lancet, 1942, 2.742) that injections of nicotine relieved the withdrawal symptoms experienced by cigarette smokers when they stopped smoking. More recently, in double-blind studies, nicotine was far superior to a placebo in suppressing or preventing the appearance of many of the signs and symptoms of withdrawal (J. R. Hughes et al., Psychopharmacology, 1984, 83:82-7; N. G. Schneider et al., Addictive Behavior, 1984, 9:149-56; R. J. West et al., Journal of Addiction, 1984, 79:215-9; K. O. Fagerstrom in Nicotine Replacement; a Critical Evaluation, O. F. Pomperleau and C. S. Pomperleau, eds., Alan R. Liss, Inc., New York, 1988, pp. 109-28,; and J. E. Henningfield and D. R. Jasinski, ibid, pp.35-61). Irritability and impatience were shown to have been reduced in at least five independent controlled studies, while anxiety and difficulty concentrating were shown to have been reduced in at least two studies. Other smoking-withdrawal symptoms for which nicotine was shown to have been significantly more effective than a placebo in relieving the condition in at least one study include depression, hunger, somatic complaints, and sociability. Nicotine has also been found to be effective in reducing anger, irritability, frustration and feelings of tension, while increasing the ability to focus upon the completion of tasks, without causing general response depression, drowsiness or sedation (R. R. Hutchinson et al., U.S. Pat. No. 3,879,794, issued Mar. 11, 1975).
One approach to alleviating the symptoms of tobacco withdrawal has been to develop more efficient methods of delivering nicotine, itself, for example, in transdermal patches (F. T. Etscorn, U.S. Pat. No. 4,597,961, issued Jul. 1, 1986). The major problem with this approach is the non-selective effects of nicotine and in particular, the stimulant effects of increasing cardiac workload and oxygen demand that nicotine has on the heart. A selective nicotine agonist would be expected to be equally efficacious in relieving withdrawal symptoms with fewer cardiovascular liabilities.
Withdrawal from addictive substances in general, regardless of which particular agent is withdrawn, is a traumatic experience characterized by anxiety and frustration. These emotional disturbances contribute to failure in therapy and, consequently, to a return to substance dependence. Although ameliorating these symptoms, including reducing anger, irritability, frustration and feelings of tension, does not eliminate the craving for the withdrawn drug, any agent improving the individual's ability to cope and to concentrate should vastly improve the chances of successfully completing withdrawal treatment.
Compounds somewhat similar to the novel therapeutic agents of the instant invention have been disclosed. The synthesis of certain 3,5-disubstituted isothiazoles has been reported by A. DeMunno and V. Bertini (Heterocycles, 1989, 29:97-102), who describe the preparation of 3,5-dimethyl isothiazole, 3-methyl-5-phenyl isothiazole, 3-methyl-5-hydroxymethyl isothiazole and 3,5-dihydroxymethyl isothiazole. Isothiazoles substituted at either the 3- or the 5-position with a heterocycle are neither disclosed nor suggested in this reference. Further, the isothiazoles disclosed by DeMunno and Bertinini have no known pharmacological activity.
Wadsworth and Jenkins in European Patent Application EP 402056, published Dec. 12, 1990, and P. A. Wyman in European Patent Application EP 413545, published Feb. 20, 1991 (both assigned to the Beecham Group) disclose certain non-aromatic 1-azabicyclic ring systems substituted in the 3-position by certain aromatic heterocycles, such as for example, triazole, tetrazole and oxadiazole. These compounds, however, are agonists at muscarinic receptors in the CNS.
Nielsen et al., in European Patent Application EP 316718, published May 24, 1989, disclose certain 3-4 dehydropiperidines substituted in the 3-position by oxazole, isoxazole, and isoxadiazole substituents for treating Alzheimer's disease, as opposed to the 2-substituted saturated ring compounds of the instant application.
Applicants have, however, discovered compounds new to the art which are useful in the treatment of the above disorders.